Hydroxyl Radical Generation Mechanism During the Redox Cycling Process of 1,4-Naphthoquinone

Airborne quinones contribute to adverse health effects of ambient particles probably because of their ability to generate hydroxyl radicals (·OH) via redox cycling, but the mechanisms remain unclear. We examined the chemical mechanisms through which 1,4-naphthoquinone (1,4-NQ) induced ·OH, and the redox interactions between 1,4-NQ and ascorbate acid (AscH₂). First, ·OH formation by 1,4-NQ was observed in cellular and acellular systems, and was enhanced by AscH₂. AscH₂ also exacerbated the cytotoxicity of 1,4-NQ in Ana-1 macrophages, at least partially due to enhanced ·OH generation. The detailed mechanism was studied in an AscH₂/H₂O₂ physiological system. The existence of a cyclic 1,4-NQ process was shown by detecting the corresponding semiquinone radical (NSQ^·–) and hydroquinone (NQH₂). 1,4-NQ was reduced primarily to NSQ^·– by O₂^·– (which was from AscH₂ reacting with H₂O₂), not by AscH₂ as normally thought. At lower doses, 1,4-NQ consumed O₂^·– to suppress ·OH; however, at higher doses, 1,4-NQ presented a positive association with ·OH. The reaction of NSQ^·– with H₂O₂ to release ·OH was another important channel for OH radical formation except for Haber-Weiss reaction. As a reaction precursor for O₂^·–, the enhanced ·OH response to 1,4-NQ by AscH₂ was indirect. Reducing substrates were necessary to sustain the redox cycling of 1,4-NQ, leading to more ·OH and a deleterious end point.